Autoimmune diseases develop when the adaptive immune response targets self-antigens, leading to inflammation and tissue destruction. The innate immune system faces the same fundamental challenge as the adaptive immune system - distinguishing self from non-self antigens - and there is now considerable evidence that recognition of self nucleic acids through toll-like receptors (TLRs) can contribute significantly t sterile inflammation and autoimmunity, with the clearest example being the role played by TLR9 and TLR7 in the pathogenesis of systemic lupus erythematosus (SLE). One of the innate receptors for RNA, TLR8, is a potent stimulator of inflammatory cytokines such as IL6 and TNF-, and its expression by multiple cell types involved in inflammatory diseases suggests likely involvement in autoimmunity. However, the lack of useful animal models, a consequence of the very different ligand specificity of human TLR8 and its rodent orthologs, has proven to be a major limitation in the study of TLR8 function. We have developed new tools that we hope will help better understand the biology of TLR8 and that have provided important new evidence for a role of TLR8 signaling in rheumatoid arthritis. The key objective of this proposal is to develop small-molecule antagonists of human TLR8 that can be tested for efficacy, first in the novel animal models we have developed, and ultimately in patients. The principal activities will include: Establishment of a cell-based screening strategy for huTLR8 antagonists. Screening multiple libraries of well-characterized compounds. Confirmation of the specificity of hits from these screening activities. If successful, this project will demonstrate the feasibility of developng a small-molecule inhibitor for human TLR8, and will provide the lead compounds that can be rigorously tested for potential use in the treatment of rheumatoid arthritis.